Imetelstat Elicits Efficacy Across Molecularly Defined Subgroups of Lower-Risk MDS

Uwe Platzbecker, MD

Treatment with imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, demonstrated clinical efficacy across molecularly defined subgroups of patients with heavily transfused, lower-risk myelodysplastic syndrome (LR-MDS) who did not harbor 5q deletions (non-del[5q]) and were relapsed/refractory to erythropoiesis-stimulating agents (ESAs), according to findings from an analysis of the ongoing phase 2/3 IMerge trial (NCT02598661).¹

Among 38 patients treated, response rates did not significantly differ between patients with International Prognostic Scoring System (IPSS)–low and intermediate-1 risk MDS or between those with very good/good– and intermediate/poor–cytogenetic risk. However, a high rate of transfusion independence (TI) and hematologic improvement–erythroid (HI-E) was observed in patients with poor–cytogenetic risk.

MDS is characterized by clonal myeloproliferation that arises from highly mutated, malignant progenitor cell clones, lead study author Uwe Platzbecker, MD, director of the Medical Clinic I at the University Hospital in Leipzig, in Leipzig, Germany, and co-authors wrote in a poster presentation of the data.

Patients with LR-MDS whose disease is relapsed/refractory to ESAs and are dependent on red blood cell transfusions represent an underserved patient population for which limited treatment options are available.

In LR-MDS, overall survival is negatively affected by higher telomerase activity, overexpression of human telomerase reverse transcriptase, and the presence of shorter telomeres.

Imetelstat is a potent, 13-mer lipid-conjugated oligonucleotide targeted toward the RNA template of human telomerase that prevents the maintenance of telomeres and has the potential to modify MDS. The agent selectively kills malignant stem and progenitor cells to enable normal blood cell production.

Findings from the phase 2 portion of the IMerge trial showed that at a median follow-up of 24 months, 42% of patients with transfusion-dependent, non-del(5q) LR-MDS whose disease was relapsed/refractory to ESAs achieved at least 8 weeks of TI, 32% achieved at least 24 weeks of TI, and 29% achieved at least 1 year of TI. Moreover, imetelstat demonstrated a tolerable safety profile in this patient population.

The goal of the present analysis, from which findings were presented during the EHA 2021 Virtual Congress, was to evaluate the efficacy of imetelstat in molecularly defined subgroups of patients with LR-MDS based on cytogenetic and mutational profiles.

Patients underwent bone marrow aspirates during screening, which were used for karyotype-based cytogenetic analysis. Mutations were analyzed in peripheral blood samples by next-generation sequencing with a 54-gene panel assay.

Among the 31 patients who had available baseline mutation data, 90.3% (n = 28) had at least 1 mutation. Moreover, 53.6% (n = 15), 28.6% (n = 8), and 17.9% (n = 5) of patients had 1, 2, and at least 3 mutations, respectively. No mutations were detected in 3 patients.

Notably, clinical response was not correlated with mutation status or number of mutations.

SF3B1 was the most frequently mutated gene, and 87.1% (n = 27) of patients harbored an SF3B1 mutation. This finding was consistent with the predominance of ring sideroblast phenotypes, which 23 patients had. Furthermore, SF3B1 hotspot mutations identified included E622D (11.1%; n = 3), R625C/L (11.1%; n = 3), H662Q (14.8%; n = 4), K666R (14.8%; n = 4), K700E (44.4%; n = 12), and G740E (3.7%; n = 1).

TI was durable in all patients who harbored hotspot SF3B1 mutations, except those with K666R alterations. HI-E responses were observed across all patients with hotspot mutations.

Further results regarding IPSS risk groups demonstrated that patients with low-risk IPSS (n = 24) had response rates of 25%, 25%, and 20.8% at 8-week TI, 24-week TI, and 1-year TI, respectively. The HI-E response rate was 58.3% in this group.

Patients with intermediate-risk IPSS (n = 14) had response rates of 78.6%, 50%, and 42.9% at 8-week TI, 24-week TI, and 1-year TI, respectively. The HI-E response rate was 85.7% in this group.

By cytogenetic risk, patients with very good/good risk (n = 28) had response rates of 35.7%, 32.1%, and 25% at 8-week TI, 24-week TI, and 1-year TI, respectively. The HI-E response rate was 60.7% in this group.

Patients with intermediate/poor cytogenetic risk had response rates of 83.3%, 50%, and 50% at 8-week TI, 24-week TI, and 1-year TI, respectively. The HI-E response rate was 100% in this group.

By number of mutations, the 8-week TI rates were 33% in patients with no mutations (n = 3), 60% in patients with 1 mutation (n = 15), 50% in patients with 2 mutations (n = 8), and 20% in patients with 3 or more mutations (n = 5). At 24-week TI, the response rates were 0%, 47%, 50%, and 20%, respectively. At 1-year TI, the response rates were 0%, 47%, 38%, and 20%, respectively. The HI-E response rates were 33%, 93%, 50%, and 60%, respectively.

By mutations with different biologic function, the response rates at 8-week TI were 33% for patients with no mutations (n = 3), 50% for patients with mutations in splicing genes (n = 28), 43% for patients with mutations in epigenetic regulators (n = 7), and 25% for patients with mutations in receptors or kinases (n = 8). At 24-week TI, the response rates were 0%, 43%, 43%, and 25%, respectively. At 1-year TI, the response rates were 0%, 39%, 29%, and 25%, respectively. The HI-E response rates were 33%, 75%, 71%, and 50%, respectively.

Finally, by SF3B1 hot spot mutation, response rates at 8-week TI were 67% for E622D mutations, 100% for R625C/L mutations, 50% for H662Q mutations, 0% for K666R mutations, 50% for K700E mutations, and 100% for G740E mutations. At 24-week TI, the response rates were 67%, 100%, 50%, 0%, 33%, and 100%, respectively. At 1-year TI, the response rates were 67%, 100%, 50%, 0%, 25%, and 100%, respectively. The HI-E response rates were 67%, 100%, 75%, 50%, 83%, and 100%, respectively.

Reference

1. Platzbecker U, Fenaux P, Eygen KV, et al. Efficacy of imetelstat is independent of molecular subtypes in heavily transfused non-del(5q) lower risk MDS (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Poster EP910.